Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells

Berger, Carole L.; Tigelaar, Robert E.; Cohen, Justine V.; Mariwalla, Kavita; Trinh, Jennifer; Wang, Nianci; Edelson, Richard L.

doi:10.1182/blood-2004-06-2181

Cited by 223 publications

(200 citation statements)

References 47 publications

(47 reference statements)

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“…This immunosuppression could be explained by either a replacement of reactive CD4 þ and CD8 þ cells by the tumor or by an immunosuppressive nature of the tumor. The latter hypothesis is supported by a recent study by Berger et al 8 suggesting that CTCL is a malignant proliferation of regulatory T cells (T reg ). This group demonstrated in an in vitro model that under certain circumstances, CTCL tumor cells could express FOXP3, currently the best marker to identify T reg .…”

Section: Introductionsupporting

confidence: 73%

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

et al. 2006

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Cutaneous T-cell lymphomas (CTCL) are mainly comprised of two variants: mycosis fungoides (MF) with CD4 þ tumor cells confined to the skin and the leukemic Sé zary syndrome with tumor cell spread to the blood. In this study, we investigated cutaneous expression of the regulatory T-cell (T reg ) marker FOXP3 in 30 CTCL patients. Immunohistochemical analysis revealed significantly lower numbers of CD4 þ FOXP3 þ cells within the dermal lymphomononuclear infiltrate of Sé zary patients (16% FOXP3 þ cells of CD4 þ cells) in contrast to MF (43% FOXP3 þ cells (Po0.05)) and rare types of CTCL (45% FOXP3 þ cells). Furthermore, CD4 þ FOXP3 þ T cells were also markedly reduced in the CD4 þ population within the peripheral blood of Sé zary patients compared to controls as determined by fluorescence-activated cell sorter, quantitative PCR and functional analyses. The data support the conclusion that the neoplastic cells in CTCL do not express the T reg marker FOXP3. Our data also identify Sé zary syndrome as, to our knowledge, the first reported neoplastic disease with a clear reduction in T reg numbers within the CD4 þ population. This lack of T reg might account for the more aggressive nature of Sé zary syndrome compared with other CTCL.

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Section: Introductionsupporting

confidence: 73%

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

et al. 2006

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“…Support for the latter hypothesis is provided by recent data demonstrating that HTLV-1 infection of CD4 + CD25 -T cells from healthy donors induces a Treg phenotype by up-regulating CD25 protein, FOXP3 mRNA expression and TGF-b secretion in CD4 + cells [30]. While there have been reports of tumoural FOXP3 expression in an in vitro model of cutaneous T cell lymphoma [31], our data from primary lymphomas do not corroborate these findings, but indicate the presence of a high percentage of "natural" Treg in the skin of mycosis fungoides patients [27,29].…”

Section: Foxp3 Expression In Tumour Cellsmentioning

confidence: 98%

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

2006

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Regulatory T cells (Treg) provide protection from autoimmune disease, graft‐versus‐host disease, transplant rejection and overwhelming tissue destruction during infections. Conversely, high Treg numbers enable cancer cells to evade the host immune response. Thus, Treg are seen as an important tool to manipulate the immune response. However, as the immunological community is trying to move this knowledge from mice to humans, contradictory results regarding the number and function of Treg in various diseases are appearing. This problem arises because we cannot clearly define Treg populations on the basis of expression of CD25 and other cell surface markers in humans. This review addresses the utility of the FOXP3 forkhead transcription factor for the identification of Treg populations and summarizes recent data on the expression of FOXP3 in lymphomas. It is crucial to really understand Treg biology before attempting therapies, including (i) the injection of expanded Treg to cure autoimmune disease or prevent graft‐versus‐host disease or (ii) the depletion or inhibition of Treg in cancer therapy. For instance, new data arising from the study of haematological malignancies highlight the additional complexity of systems where malignant cell populations may also be direct Treg targets.

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“…Studies of CTCL cell lines have shown dysregulation of T-cell activation including constitutive IL-2Ra expression, 13 spontaneous IL-5 production, 14 enhanced secretion of IL-10 (ref. 51) and aberrant expression of IL-17. 52 In classical Hodgkin's lymphoma, HSP90 is essential for JAK/STAT signalling, as it activates JAK1 and JAK2.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

et al. 2011

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Constitutive and persistent activation of STAT3 has been implicated in the pathogenesis of many malignancies. Studies of CTCL cell lines have previously suggested that aberrant activation of STAT3 is mediated via silencing of the negative regulator SHP-1 by promoter methylation. In this study of ex vivo tumour cell populations from 18 Sé zary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4 þ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylationspecific PCR analysis of the SHP-1 CpG island in 47 SS patients and 11 healthy controls did not detect any evidence of methylation. Moreover, small interfering RNA knockdown of SHP-1 had no effect on phosphorylation of STAT3. In contrast, treatment of SS tumour cells with the pan-JAK inhibitor pyridone 6 led to downregulation of phosphorylated STAT3 (pSTAT3), its target genes and induction of apoptosis. No evidence for common JAK1/JAK2-activating mutations was found. These data demonstrate that constitutive activation of STAT3 in SS is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members.

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Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells

Cited by 223 publications

References 47 publications

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

FOXP3⁺ regulatory T cells: Current controversies and future perspectives

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

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Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells

Cited by 223 publications

References 47 publications

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas

FOXP3+ regulatory T cells: Current controversies and future perspectives

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

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FOXP3⁺ regulatory T cells: Current controversies and future perspectives